Opioid use disorder (OUD) and its consequences are a major public health concern and have recently been declared a national public health emergency. Despite the availability of medications to treat OUD, there is a need for improved treatment modalities that involve other mechanisms of action. Current pharmacologic treatment options all target the mu-opioid receptor, either as a full agonist (methadone), partial agonist (buprenorphine), or antagonist (naltrexone). While these medications have demonstrated efficacy and safety, they also have limitations. Full and partial agonists have abuse liability, and significant levels of misuse, abuse, and diversion have been observed in the US and internationally (Lofwall 2014; Yokell 2012). This has resulted in restrictions on access due to a lack of waivered prescribers and patient limits on prescribing for buprenorphine and dispensing through federally regulated opioid treatment programs requiring daily observed buprenorphine. In addition, there are concerns about methadone overdose. Naltrexone requires abstinence from opioids prior to initiation of treatment, which is a barrier to treatment for many patients. Of the 2.1 million people suffering from OUD in the US, only 20% seem to receive any form of treatment and many of those who are treated with these medications do not achieve abstinence from opioid use and fail to achieve recovery (Saloner 2015). Thus, there is a need for additional pharmacologic treatment options, particularly for medications without abuse liability and that do not require completion of withdrawal from opioids prior to treatment. Nonclinical studies support a role for the orexin system in drug seeking, as compounds that selectively block signaling at the orexin-1 receptor (OX1R) reduce seeking of multiple drugs of abuse (James 2017). C4X3256, a Non-Opioid, Highly-Selective OX1R Antagonist has been shown to have a long residence time at the OX1R, and also reduce intravenous self- administration and cue-induced reinstatement in animal models of nicotine addiction, suggesting it could be a treatment for a range of addiction related behaviors. Studies proposed in the application will move C4X3256 from preclinical development through Phase I testing, including up to 7 days dosing in healthy volunteers and up to 28 days dosing in subjects with OUD. The current toxicology studies will support the administration of C4X3256 to human volunteers for 4 weeks. Additional toxicology studies are proposed to allow for extended dosing duration in phase II and for women of childbearing potential to participate in Phase II outpatient trials. Thus, the clinical, preclinical and supporting pharmaceutical development studies proposed will allow C4X3256 to move to Phase II studies.